title: Molecular basis of a new type of C1q-deficiency associated with a non-functional low molecular weight (LMW) C1q: parallels and differences to other known genetic C1q-defects.
abstract: Analysis of an abnormal C1q molecule of individuals of a Moroccan family by ultracentrifugation in sucrose gradients revealed a low molecular weight C1q (LMW-C1q). We investigated the molecular basis of this defect by sequencing all six exons of the three C1q genes. One point mutation in the codon for Gly at position 15 (GGT) of the B chain was found resulting in an amino acid substitution to Asp (GAT). The exchange not only leads to an interruption of the collagen-like motif Gly-X-Y, but also introduces one negatively charged residue per B chain which results in two additional charges per structural subunit (A-B, C-C, A-B). The mutation which has been identified by DNA-sequencing in the C1q-deficient younger brother of the propositus was confirmed by PCR-EcoRV-RFLP in the sister and the propositus himself. This mutation is very similar to a mutation previously described in another case of functional C1q deficiency where Gly at position 6 of the C chain was substituted by a large positively charged residue (Arg). Again, a LMW-C1q was demonstrated. These point mutations that lead to amino acid substitutions result in the production of a LMW-C1q where the formation of functionally active 11S C1q consisting of three structural subunits appears to be inhibited by the introduction of six additional charges, one per B or C chain, respectively, in the collagenous region of the molecule.
authors.affiliation: Institut für Medizinische Mikrobiologie und Hygiene, Johannes Gutenberg Universität, Mainz, Germany. petrf000@goofy.zdv.uni-mainz.de
authors.forename: F
authors.initials: F
authors.lastname: Petry
authors.forename: G
authors.initials: G
authors.lastname: Hauptmann
authors.forename: J
authors.initials: J
authors.lastname: Goetz
authors.forename: E
authors.initials: E
authors.lastname: Grosshans
authors.forename: M
authors.initials: M
authors.lastname: Loos
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D003094:Collagen / Q000737:chemistry / Q000235:genetics; D015922:Complement C1q / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D015941:Complement Hemolytic Activity Assay; D004247:DNA / Q000235:genetics; D005091:Exons; D005260:Female; D006801:Humans; D005779:Immunodiffusion; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D008970:Molecular Weight; D009018:Morocco; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017421:Sequence Analysis
chemical_list: D015922:Complement C1q; D003094:Collagen; D004247:DNA